Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science.

OBJECTIVES: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Consensus discussion of the committee. RESULTS: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. CONCLUSIONS: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.

Comparison of micronized fenofibrate and pravastatin in patients with primary hyperlipidemia.

Micronized fenofibrate lowers total cholesterol and low-density lipoprotein cholesterol to a similar extent as statins but raises high-density lipoprotein cholesterol and lowers triglycerides to a greater extent. The comparative lipid-modifying efficacy of micronized fenofibrate and pravastatin has not been evaluated in dyslipidemic patients. This prospective, multicenter, randomized trial compared the efficacy of 3 months' treatment with micronized fenofibrate (200 mg once daily) or pravastatin (20 mg once daily) in hypercholesterolemic type IIa and mixed dyslipidemic type IIb patients. Two hundred sixty-five male and female patients (18-75 years) were recruited from 28 European centers, and 151 were analyzed. Micronized fenofibrate was at least as effective as pravastatin in reducing levels of low-density lipoprotein cholesterol and total cholesterol in primary dyslipidemia but was significantly more effective than pravastatin in raising high-density lipoprotein cholesterol (respectively, 13.2% vs. 5.6%; p = 0.0084) and lowering triglycerides (-38.7% vs. -11.8%; p = 0.0001). In type IIa dyslipidemia, micronized fenofibrate was as effective as pravastatin in raising high-density lipoprotein cholesterol (+8.6% vs. +8.0%) but was fivefold more effective in lowering triglycerides (-34.3% vs. -7.2%; p = 0.0001). In type IIb dyslipidemic patients with low baseline high-density lipoprotein cholesterol levels, micronized fenofibrate was 10-fold and nearly 3-fold superior to pravastatin in raising high-density lipoprotein cholesterol and lowering triglycerides, respectively. Micronized fenofibrate may be considered an effective first-line therapy for patients with primary hyperlipidemia, particularly those with type IIb mixed dyslipidemia or type 2 diabetes.

Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.

BACKGROUND: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. METHODS: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. RESULTS: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. CONCLUSION: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.